Abstract

The dynamic ligand design (DLD) algorithm, an automated method for the creation of novel ligands, links up small functional groups that have been placed in energetically favorable positions in the binding site of a target molecule. The positions and orientations of the small functional groups can be determined using the multi-copy simultaneous search approach (MCSS) or experimental data. In this work the original DLD methodology is extended by using a modified version of the pseudo-potential energy function. A novel simulated annealing protocol is presented for optimizing the pseudo-potential energy of ligands in the binding site; the protocol is expected to be applicable to other optimization problems. The utility of the method is illustrated by designing an inhibitor for endothiapepsin. The binding affinity of the inhibitor is assessed using a thermodynamic cycle that decomposes the binding free energy into a sum of translational, rotational, configurational, hydrophobic, and electrostatic contributions. The calculations suggest that the designed molecule will bind endothiapepsin with high affinity.